This invention was made with support from the National Institute of Health, grant numbers AI 12069 and R23 AI 23992. The U.S. Government has rights in the invention.
This invention concerns alteration of the interaction of a T-cell receptor and a protein-tyrosine kinase.
T-cells express cell surface antigens, e.g., CD4 and CD8, which are implicated in regulation of T-cell activation and in the association and recognition of specific antigens. CD4, which is a polypeptide antigen of 55 kDa, appears to serve as a receptor for the human immunodeficiency virus (HIV). Maddon et al., 47 Cell 333, 1988, Sleckman et al., 328 Nature 35l, 1987. Structurally, the CD4 antigen is a member of an immunoglobulin superfamily (Maddon et al., 42 Cell 93, 1985) and appears capable of regulating the proliferation of the CD4 subset of T-cells. CD8 has a molecular weight of 32 kDa and is also a member of the immunoglobulin superfamily. It appears to be involved in the recognition of major histocompatibility complex (MHC) class I antigens. It defines a separate population of T-cells distinct from the CD4 subset. The CD4 and CD8 antigens may also regulate the activation of T-cells, either individually, or in conjunction with the antigen CD3-Ti present on the surface of T-cells.
Protein-tyrosine kinases (PTKs) play a role in activation and transformation of mammalian cells. For example, oncogenic transformation by Rous sarcoma virus is mediated by the PTK, pp 60.sup.src. Several retroviral oncogenes are homologous to pp 60.sup.src and together form a family of src-like PTKs. These include v-abl, v-erb, v-fes/fps, v-fgr, v-src and v-yes. Also within this family are the receptors for epidermal growth factor, platelet-derived growth factor, and insulin. Another homologous protein kinase, termed pp 56.sup.lck (or P56.sup.Lstra, p 58.sup.lck) has been identified in murine T-cells (Marth et al., 43 Cell 393, 1985), as has its homolog in human T lymphocytes (Trevillyan et al., 888 Bioc. Biop. Acta. 286, 1986, and Koga et al., 16 Eur. J. Immumol. 1643, 1986). pp 56.sup.lck may decrease in amount in T-cells after their activation, however its role in the process is unknown.